Alpha motor neuron death in spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN) protein. SMN interacts with proteins known to participate in RNA processing, apoptosis and axonal transport. However, why SMN loss results in anterior horn cell death is still unknown. Our analyses of SMN deficient neuronal cells discovered that low levels of SMN are associated with a significant down regulation in alpha-synuclein (SNCA) expression. The 140-amino acid protein is strongly expressed in neurons of the central nervous system, particularly in synapses. Recent work has indicated a possible neuroprotective role for SNCA, as well as indicating that down regulation of SNCA can compromise viability in neural cells. This proposal will first determine whether the dramatic decrease in SNCA correlates with SMN level in neural cells. This will be performed in motor neuron progenitor cells derived from both a mouse embryonic stem cell. Secondly, the proposal will investigate whether a decrease of SNCA in neuronal cells will cause similar cellular dysfunction to that observed in SMA cells. Thirdly, we will attempt to rescue SMN hypomorphic neuronal cells from degeneration by over-expressing SNCA. Lastly, we will determine whether increasing SNCA expression can attenuate disease progress in an animal model of SMA. This work will yield information about the downstream effects of SMN depletion in neural cells with important implications for the discovery of new therapeutic interventions. Determining SNCA levels in human cells may also lead to the development of a new biomarker for the disease. PUBLIC HEALTH RELEVANCE: The overarching goal of this application is to learn more about potentially significant downstream markers of spinal muscular atrophy pathology. The knowledge gained from this proposal concerning our recent observation of significant regulation of alpha-synuclein in spinal muscular atrophy models, used alone or in combination with existing clinical outcome measures, is a highly desirable goal potentially allowing us to employ more accurate disease markers for future clinical trials, as well as develop novel in vitro and in vivo models for neuromuscular disease research.